Etherified hydroxy quinazolone compounds

ABSTRACT

A compound of the formula ##STR1## in which R 1  denotes optionally substituted lower alkyl which is optionally branched at the linking carbon atom, R 2  represents hydrogen or lower alkanoyl and R 3  is a group of the formula --R 3   a  --(R 3   b ) n  -- (Ia), in which R 3   a  represents the radical of the formula --N(R 4 )-- or --O-- and R 4  represents hydrogen or lower alkyl, R 3   b  denotes the radical of the formula --CH 2  -- or, if R 3   a  represents --N(R 4 )--, denotes the radical of the formula --C(═O)-- and n represents nought or 1, and a group of the formula Ia, in which n represents 1, can be linked to the carbonyl group of the carbamoyl grouping either via the group R 3   a  or the group R 3   b , or acid addition salts thereof, which can be used pharmaceutically can be used as beta-receptor blocking agents for the treatment of disorders in the cardiac rhythm and coronary heart diseases. These compounds also possess a cardio-stimulating action; some of them also display alpha-receptor-blocking properties.

This is a continuation-in-part of our copending application Ser. No.751,233 filed Dec. 16, 1976, now U.S. Pat. No. 4,140,789 granted Feb.20, 1979.

The present invention relates to etherified hydroxybenzodiheterocycliccompounds, especially compounds of the formula ##STR2## in which R₁denotes optionally substituted lower alkyl which is optionally branchedat the linking carbon atom, R₂ represents hydrogen or lower alkanoyl andR₃ is a group of the formula --R₃ ^(a) --(R₃ ^(b))_(n) -- (Ia), in whichR₃ ^(a) represents the radical of the formula --N(R₄)-- or --O--0 and R₄represents hydrogen or lower alkyl, R₃ ^(b) denotes the radical of theformula --CH₂ -- or, if R₃ ^(a) represents --N(R₄)--, denotes theradical of the formula --C(═O)-- and n represents nought or 1, and agroup of the formula Ia, in which n represents 1, can be linked to thecarbonyl group of the carbamoyl grouping either via the group R₃ ^(a) orthe group R₃ ^(b), or salts thereof and processes for the manufacture ofthese compounds and also pharmaceutical formulations containingcompounds of the formula I, or salts thereof which can be usedpharmaceutically, and the use of these compounds, preferably in the formof pharmaceutical formulations.

Lower alkyl R₁ preferably has from 2 to 5 carbon atoms and is, aboveall, ethyl, isopropyl or tert.-butyl but can also be sec.-butyl or2-methyl-2-butyl.

Substituentes of lower alkyl R₁ are, for example, aryl or aryloxy, inwhich aryl denotes an optionally substituted aromatic radical, above alloptionally substituted phenyl. Substituted phenyl contains, for example,lower alkyl, hydroxyl, lower alkoxy, methylenedioxy, halogen and/oroptionally N-substituted carbamoyl as substituents and 1 to 3 of thesesubstituents can be present and these can either be identical ordifferent.

Substituted lower alkyl R₁ is therefore aryl-lower alkyl oraryloxy-lower alkyl which is optionally branched at the linking carbonatom, and especially phenyl-lower alkyl or phenoxy-lower alkyl which isoptionally substituted in the phenyl radical, for example as indicated,and optionally branched at the linking carbon atom, such ascorresponding 1-phenyl- or 1-phenoxy-2-propyl or 4-phenyl- or4-phenoxy-2-butyl, but in addition also 2-phenyl-ethyl, or2-phenoxy-ethyl, which are optionally substituted in the phenyl radical,for example as indicated, and in which a substituted radical can besubstituted, for example, by lower alkyl, hydroxyl, lower alkoxy,methylenedioxy, halogen and/or optionally N-substituted carbamoyl.

In the context of the present description, radicals or compoundsdesignated as "lower" contain, unless otherwise defined, preferably upto 7 and above all up to 4 carbon atoms.

Unless specifically defined as above for R₁ lower alkyl is, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl,tert.-butyl, n-pentyl, 1-methyl-2-butyl or neopentyl.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, n-butoxy orisobutoxy.

Halogen is, above all, halogen with an atomic number of up to 35, thatis to say fluorine or bromine and especially chlorine.

Carbamoyl is preferably N-unsubstituted but can also be, for example,N-lower alkyl-carbamoyl or N,N-di-lower alkylcarbamoyl, for exampleN-methylcarbamoyl, N-ethylcarbamoyl or N,N-dimethylcarbamoyl.

Lower alkanoyl is, for example, acetyl or propionyl but above allpivaloyl.

Salts of compounds of the formula I are above all acid addition saltsand especially non-toxic acid addition salts, which can be usedpharmaceutically, with suitable inorganic acids, such as hydrochloricacid, hydrobromic acid, sulphuric acid or phosphoric acid, or withsuitable organic aliphatic, cycloaliphatic, aromatic, araliphatic orheterocyclic carboxylic acids or sulphonic acids, such as formic acid,acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid,malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid,fumaric acid, pyruvic acid, benzoic acid, anthranilic acid,4-hydroxybenzoic acid, salicylic acid, phenylacetic acid, embonic acid,methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonicacid, ethylenesulphonic acid, 4-chlorobenzenesulphonic acid,toluenesulphonic acid, naphthalenesulphonic acid, sulphanilic acid orcyclohexylaminesulphonic acid.

Because of the close relationships between the new compounds in the freeform and in the form of their salts, the free compounds, and the salts,are, where appropriate, also to be understood to include thecorresponding salts or free compounds respectively, in respect ofgeneral sense and intended use.

The new compounds can be in the form of racemates or of antipodes.

The new compounds display valuable pharmacological properties, inparticular strong and long-lasting beta-receptor-blocking actions, whichcan be demonstrated with the aid of corresponding pharmacologicalexperiments (see, for example, Meier et al., Arzneimittelforschung,volume 20, page 1890 (1970)). Thus, in a concentration range of fromabout 0.001 μg/ml to about 1 μg/ml the new compounds inhibit theisoproterenol tachycardia in an isolated guinea-pig heart (according toLangendorff) and in a dosage range of from about 0.0003 mg/kg to about0.3 mg/kg they inhibit the isoproterenol tachycardia and vasodilatationin narcotised cats on intravenous administration.

Some of the new compounds are cardioselective beta-receptor-blockers,i.e. they inhibit the cardial effects isoproterenol rather than thevascular effects.

The new compounds can therefore be used as beta-receptor-blockingagents, for example for the treatment of disorders in the cardiac rhythm(arrhytmia) and coronary heart diseases, such as angina pectoris, andalso as hypotensive agents in the treatment of hypertension. Moreover,these compounds also possess a cardio-stimulating action, which can bedemonstrated, for example, in a concentration range of from about 0.003to about 3 μg/ml on an isolated atrium of a guinea-pig as an increase inthe heart rate and in the myocardial contractility. This mode of actioncan also be demonstrated in a dosage range of from about 0.0003 to about0.3 mg/kg, administered intravenously, on narcotised cats in the form ofan increase in the heart rate and in the maximum rate of the increase inpressure (dP/dt) in the left ventricle. Compounds having such acardio-stimulating action therefore have a less adverse effect on thefunction of the heart than substances which do not possess theseadditional properties.

Some of these compounds also display alpha-receptor-blocking propertieswhich, for example, manifest themselves, in a concentration range offrom about 0.03 to about 3 μg/ml, as an inhibition of anoradrenalin-induced vasoconstriction in a rat mesenteric bed which isperfused in isolation.

Furthermore, some compounds have a hypertension-lowering action whenadministered intravenously in the dosage range of 0.03 to 3 mg/kg to thenarcotised cat.

A hypotensive action, for example, can be promoted by this component ofthe action.

The invention relates above all to compounds of the formula I in whichR₁ denotes lower alkyl with 2-5 carbon atoms which is optionallybranched at the linking carbon atom and can be substituted, on a carbonatom other than the linking carbon atom, by phenyl which optionallycontains hydroxyl, as well as lower alkyl, for example methyl, loweralkoxy, for example methoxy, methylenedioxy or halogen, for examplechlorine or by phenoxy which optionally contains hydroxyl or carbamoyl,R₂ represents hydrogen and R₃ represents the group of the formula Ia inwhich R₃ ^(a) denotes the radical of the formula --NH-- or --O-- as wellas --NR₄ --, in which R₄ represents lower alkyl, and R₃ ^(b) and n havethe abovementioned meanings and a group of the formula Ia, in which nrepresents 1, can be linked to the carbonyl grouping either via theradical R₃ ^(a) or the radical R₃ ^(b), or salts, especially acidaddition salts which can be used pharmaceutically, of such compounds.

The invention relates in particular to compounds of the formula I inwhich R₁ denotes lower alkyl with 2-5 carbon atoms which is optionallybranched at the linking carbon atom or denotes 2-phenyl-lower alkyl, inwhich lower alkyl contains up to 3 carbon atoms, which is optionallysubstituted in the phenyl part by hydroxyl or lower alkoxy, for example,methoxy or methylenedioxy, or denotes 2-phenoxy-lower alkyl, in whichlower alkyl contains up to 3 carbon atoms, which is substituted in thephenoxy part by hydroxyl or carbamoyl, R₂ represents hydrogen and R₃denotes the group of the formula Ia, in which R₃ ^(a) represents theradical of the formula --O-- and --N(R₄)--, in which R₄ representshydrogen or lower alkyl with up to 4 carbon atoms, and R₃ ^(b) and nhave the above-mentioned meanings and a group of the formula Ia, inwhich n represents 1, can be linked to the carbonyl grouping either viathe radical R₃ ^(a) or the radical R₃ ^(b), or salts, especially acidaddition salts which can be used pharmaceutically, of such compounds.

The invention relates in particular to compounds of the formula I inwhich R₁ denotes lower alkyl with 2-4 carbon atoms which is optionallybranched at the linking atom, especially isopropyl or tert.-butyl, ordenotes 2-phenyl-lower alkyl in which lower alkyl contains up to 3carbon atoms, which is optionally substituted in the phenyl part bylower alkoxy, for example methoxy, or methylenedioxy, or denotes2-phenoxy-lower alkyl in which lower alkyl contains up to 3 carbon atomswhich is substituted in the phenoxy part by hydroxyl and R₃ denotes thegroup of the formula Ia, in which R₃ ^(a) represents the radical of theformula --O-- and especially --NH--, and also --NCH₃ -- or --N--[(CH₂)₃--CH₃ ]--, and R₃ ^(b) and n have the abovementioned meanings and agroup of the formula Ia, in which n represents 1, can be linked to thecarbonyl grouping either via the radical R₃ ^(a) or the radical R₃ ^(b),or salts, especially acid addition salts which can be usedpharmaceutically, of such compounds.

The invention relates specifically to the compounds of the formula Idescribed in the examples, or salts, especially acid addition saltswhich can be used pharmaceutically, of such compounds.

The new compounds of the present invention can be manufactured in amanner which is in itself known.

Thus, the new compounds can be obtained, for example, when a compound ofthe formula ##STR3## is reacted with a compound of the formula R-X₃(III), in which one of the groups X₁ and X₃ represents a reactiveesterified hydroxyl group and the other represents a primary amino groupand X₂ represents hydroxyl or lower alkanoyloxy, or in which X₁ and X₂together denote the epoxy group and X₃ represents a primary amino group,and, if desired, a resulting compound is converted into another compoundof the formula I and/or, if desired, a resulting free compound isconverted into a salt or a resulting salt is converted into a freecompound and/or, if desired, a resulting racemate is resolved into theantipodes.

A reactive esterified hydroxyl group X₁ or X₃ is a hydroxyl groupesterified by a strong acid, especially a strong inorganic acid, such asa hydrogen halide acid, especially hydrochloric acid, hydrobromic acidor hydriodic acid, or sulphuric acid, or a strong organic acid,especially a strong organic sulphonic acid, such as an aliphatic oraromatic sulphonic acid, for example, methanesulphonic acid,4-methylphenylsulphonic acid or 4-bromophenylsulphonic acid, andrepresents, above all, halogen, for example chlorine, bromine or iodine,or sulphonyloxy with aliphatic or aromatic substituents, for examplemethylsulphonyloxy or 4-methylphenylsulphonyloxy.

The above reaction is carried out in a manner which is in itself knownand, especially when using a starting material containing a reactiveesterified hydroxyl group, is advantageously carried out in the presenceof a basic agent, such as an inorganic base, for example, an alkalimetal carbonate or hydroxide or alkaline earth metal carbonate orhydroxide, or an organic basic agent, such as an alkali metal loweralkanolate, and/or of an excess of the basic reactant and usually in thepresence of a solvent or solvent mixture and, if necessary, with coolingor warming, for example in a temperature range of from about -20° toabout +150°, in an open or closed vessel and/or in an inert gasatmosphere, for example, in a nitrogen atmosphere.

The starting materials of the formula II can be manufactured in a mannerwhich is in itself known, for example by converting the phenolichydroxyl group in a compound which corresponds to the starting materialof the formula II and has a free phenolic hydroxyl group in place of anetherified hydroxyl group, or the phenolic hydroxyl group in a precursorthereof, which may be monocyclic, into the allyloxy group and convertingthe latter into the desired group of the formula X₁ --CH₂ --CH(X₂)--CH₂--O-- (IIa). Thus, it is possible, for example, to convert the phenolichydroxyl group in a di-lower alkyl 3-hydroxy-phthalate into an allyloxygroup by treatment with an allyl halide, for example allyl bromide, inthe presence of a suitable base, such as an alkali metal carbonate, forexample potassium carbonate, to liberate 3-allyloxy-phthalic acid fromthe ester by hydrolysis, for example by treatment with an alkali metalhydroxide, and to convert the acid into the corresponding anhydride, forexample by treatment with acetic anhydride. Modified Curtius degradationof 3-allyloxy-phthalic anhydride, which is thus obtainable, for exampleby treatment with a suitable azide compound, such as a tri-loweralkylsilyl azide, especially trimethylsilyl azide, gives, on subsequenthydrolysis, 4-allyloxy-benzimidazol-2-one. The allyl group is convertedinto the desired 2,3-epoxy-propyl group, for example by oxidation withhydrogen peroxide or a suitable inorganic or organic per-acid, forexample 3-chloroperbenzoic acid; this group can be converted into a2-hydroxy-3-(reactive hydroxyl)-propyl group by treating thecorresponding compound with a suitable strong acid, such as a hydrogenhalide acid, and the hydroxyl group in this group can, if desired, beconverted into a lower alkanoyloxy group, for example by treatment witha suitable reactive derivative, such as an optionally mixed anhydride,of a lower alkanecarboxylic acid.

A further process for the manufacture of compounds of the formula I inwhich R₁ denotes a lower alkyl radical which is optionally substitutedand contains a hydrogen atom on the linking carbon atom consists inreducing the grouping of the formula R_(o) ═N-- (IVa) in a compound ofthe formula ##STR4## in which R_(o) represents the optionallysubstituted lower alkylidene radical which corresponds to an optionallysubstituted lower alkyl radical R₁, to the grouping of the formula R₁--NH-- (IVb) and, if desired, carrying out the additional process steps.

The above conversion, by reduction, of a radical of the formula IVa intothe desired grouping of the formula IVb can be carried out in a mannerwhich is in itself known and suitable reducing agents which can be usedare, in particular, light metal hydride reducing agents, such as alkalimetal borohydrides, for example sodium borohydride, and alkali metalcyanoborohydrides, for example sodium cyanoborohydride, or boronhydrides, for example diborane, and also catalytically activatedhydrogen, such as, for example, hydrogen in the presence of a heavymetal catalyst, for example Raney nickel, platinum oxide or palladium.

The above reductions are carried out in a manner which is in itselfknown, usually in the presence of an inert solvent and, if necessary,with cooling or warming, for example in a temperature range of fromabout -20° to about +150°, and/or in a closed vessel under pressureand/or in an inert gas atmosphere, for example a nitrogen atmosphere.

The starting materials of the formula IV can be obtained in a mannerwhich is in itself known by, for example, converting the phenolichydroxyl group in a compound which corresponds to the starting materialof the formula IV and has a free phenolic hydroxyl group in place of anetherified phenolic hydroxyl group, or the phenolic hydroxyl group in aprecursor thereof, which may be monocyclic, into the allyloxy group andconverting the latter, via the 2,3-epoxy-propoxy group and the3-amino-2-hydroxy-propoxy group, into the desired group of the formulaR_(o) ═N--CH₂ --CH(OR₂)--CH₂ --O-- (IVc). Thus, a preferred startingmaterial can be obtained, for example, by treating(2,3-epoxy-propoxy)-benzimidazol-2-one with ammonia and reacting the(3-amino-2-hydroxy-propoxy)-benzimidazol-2-one which is thus obtainablewith a carbonyl compound of the formula R_(o) ═O (VI), in which R_(o)has the abovementioned meaning. At a suitable stage, the hydroxyl groupcan be converted into a lower alkanoyloxy group, for example bytreatment with a suitable reactive derivative, such as an optionallymixed anhydride, of a lower alkanecarboxylic acid.

It is possible to effect the manufacture of the starting material of theformula IV at the same time as the conversion thereof into the desiredcompound of the formula I if the reaction of the amino compound with thecarbonyl compound is carried out in the presence of a suitable reducingagent. Thus, for example,4-(3-amino-2-hydroxy-propoxy)-benzimidazol-2-one can be reacted withacetone in the presence of catalytically activated hydrogen or,preferably, of a hydride reducing agent, for example sodiumcyanoborohydride, and a desired compound of the formula I, in which R₁represents isopropyl, is obtained direct.

The new compounds of the formula I in which R₂ represents hydrogen canalso be obtained when X₄ and/or X₅ in a compound of the formula ##STR5##in which at least one of the groups X₄ and X₅ denotes a group which canbe replaced by hydrogen and the other represents hydrogen or representsa group which can be replaced by hydrogen, or X₄ and X₅ togetherrepresent a radical which can be split off and can be replaced by twohydrogen atoms linked to the oxygen or nitrogen atom, or in a saltthereof, are replaced by hydrogen and, if desired, the additionalprocess steps are carried out.

In a phenyl or phenoxy group substituted by hydroxyl, both beingsubstituents of R₁, the hydroxyl group can optionally be in a formprotected by a group X₄ or X₅, this group X₄ or X₅ being replaced byhydrogen either at the same time as, or subsequent to, the describedprocess.

The groups X₄ and/or X₅ are split off by means of solvolysis orreduction. In the abovementioned starting materials of the formula VI,X₄ is preferably a group which can be replaced by hydrogen whilst X₅above all represents hydrogen.

A particularly suitable group X₄ which can be split off is, above all,an α-aryl-lower alkyl group which can be split off hydrogenolytically,such as an optionally substituted 1-phenyl-lower alkyl group, in whichsubstituents, especially in the phenyl part, can be, for example, loweralkyl, such as methyl or tert.-butyl, hydroxyl, lower alkoxy, such asmethoxy, halogen, for example chlorine or bromine, and/or nitro, andabove all benzyl. A group X₄ can also represent a radical which can besplit off by solvolysis, such as hydrolysis or acidolysis, and also aradical which can be split off by reduction, including byhydrogenolysis, especially a corresponding acyl radical, such as theacyl radical of an organic carboxylic acid, for example lower alkanoyl,such as acetyl, or aroyl, such as benzoyl, and also the acyl radical ora half-ester of carbonic acid, such as lower alkoxycarbonyl, for examplemethoxycarbonyl, ethoxycarbonyl or tert.-butoxycarbonyl,2-halogeno-lower alkoxycarbonyl, for example2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionallysubstituted 1-phenyl-lower alkoxycarbonyl, for example benzyloxycarbonylor diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, for examplephenacyloxycarbonyl, or the acyl radical of an organic sulphonic acidsuch as of an aromatic sulphonic acid, above all an optionallysubstituted phenylsulphonyl radical, in which substituents have, forexample, the meaning indicated for the 1-phenyl-lower alkyl radicalabove, and especially 4-methylphenylsulphonyl, and also an optionallysubstituted 1-polyphenyl-lower alkyl group, in which substituents, aboveall in the phenyl part, have for example, the abovementioned meanings,and above all trityl.

A group X₅ which can be replaced by hydrogen is preferably also a groupwhich can be split off by hydrogenolysis, such as one of theabovementioned optionally substituted 1-phenyl-lower alkyl groups andabove all benzyl. It can also be one of the acyl groups which can besplit off by solvolysis, including alcoholysis, or reduction and hasbeen mentioned for the group X₄, and also an optionally substitutedaliphatic or araliphatic hydrocarbon radical which is poly-branched atthe linking carbon atom, such as tert.-lower alkyl, for exampletert.-butyl, or trityl.

A radical which is formed by X₄ and X₅ together and can be split off is,above all, again a group which can be split off by hydrogenolysis, suchas optionally substituted 1-phenyl-lower alkylidene, in whichsubstituents can be, for example, lower alkyl, such as tert.-butyl,hydroxyl, lower alkoxy, halogen and/or nitro, and especiallybenzylidene, as well as groups which can be split by solvolysis, andespecially by hydrolysis, such as lower alkylidene, for examplemethylene or isopropylidene, or cycloalkylidene, for examplecyclohexylidene. A further radical which is formed by the groups X₄ andX₅ together is the diacyl radical of carbonic acid or thiocarbonic acid,that is to say the carbonyl group or the thiocarbonyl group.

Starting materials which can be used in the form of salts are, aboveall, used in the form of acid addition salts, especially ofcorresponding salts with inorganic acids, for example mineral acids, aswell as with organic acids.

Radicals X₄ and/or X₅ which can be split off by hydrogenolysis,especially optionally substituted 1-phenyl-lower alkyl groups and alsosuitable acyl groups, such as optionally substituted 1-phenyl-loweralkoxycarbonyl, as well as optionally substituted 1-phenyl-loweralkylidene groups formed by the groups X₄ and X₅ together can be splitoff by treatment with catalytically activated hydrogen, for example withhydrogen in the presence of a nickel catalyst, such as Raney nickel, orof a suitable noble metal catalyst.

Groups X₄ and/or X₅ which can be split off by hydrolysis, such as acylradicals of organic carboxylic acids, for example lower alkanoyl, andhalf-esters of carbonic acid, for example lower alkoxycarbonyl, andalso, for example, trityl radicals, as well as lower alkylidene groups,or a carbonyl group, formed by the radicals X₄ and X₅ together, can,depending on the nature of such radicals, be split off by treatment withwater under acid and/or basic conditions, for example in the presence ofa mineral acid, such as hydrochloric acid or sulphuric acid, or of analkali metal hydroxide or carbonate or alkaline earth metal hydroxide orcarbonate.

Radicals which can be split off by acidolysis are, in particular,certain acyl radicals of half-esters of carbonic acid, such as, forexample, tert.-lower alkoxycarbonyl or optionally substituteddiphenylmethoxycarbonyl radicals and also tert.-lower alkyl radicals X₅; they can be split off by treatment with suitable strong organiccarboxylic acids, such as lower alkanecarboxylic acids which areoptionally substituted by halogen, especially fluorine, and above allwith trifluoroacetic acid (if necessary in the presence of an activatingagent, such as anisole), and also with formic acid.

Radicals X₄ and/or X₅ which can be split off by reduction are alsounderstood as those groups which are split off on treatment with achemical reducing agent (especially with a reducing metal or a reducingmetal compound). Such radicals are, in particular, 2-halogeno-loweralkoxycarbonyl or aroylmethoxycarbonyl, which can be split off, forexample, on treatment with a reducing heavy metal, such as zinc, or witha reducing heavy metal salt, such as a chromium-II salt, for examplechromium-II chloride or chromium-II acetate, usually in the presence ofan organic carboxylic acid, such as formic acid or acetic acid, and ofwater. Arylsulphonyl radicals which can be split off by reduction andespecially those which above all represent the radical X₄ can bereplaced by hydrogen, for example on treatment with an alkali metal, forexample lithium or sodium, in ammonia, or by means of electrolyticreduction.

The above reactions are carried out in a manner which is in itselfknown, usually in the presence of a solvent or solvent mixture, it alsobeing possible for suitable reactants at the same time to act assolvents, and, if necessary with cooling or warming, for example in atemperature range of from about -20° to about +150°, in an open orclosed vessel and/or in an atmosphere of an inert gas, for examplenitrogen.

The starting materials of the formula VI can be manufactured in a mannerwhich is in itself known, for example by treating a compound of theformula ##STR6## with a compound of the formula R₁ -X₇ ^(o) (VIII), inwhich X₅ ^(o) has the meaning indicated above for X₅ and one of thegroups X₆ ^(o) and X₇ ^(o) represents a reactive esterified hydroxylgroup and the other represents the group of the formula --NH(X₄), inwhich X₄ has the abovementioned meaning, with the proviso that at leastone of the groups X₄ and X₅ differs from hydrogen, or in which X₅ ^(o)and X₆ ^(o) together form a bond and X₇ ^(o) represents the group of theformula --NH(X₄), in which X₄ differs from hydrogen. The above reactionsare carried out in a manner which is in itself known.

The new compounds of the present invention can also be obtained when theradicals X₈ and X₉ are split off from a compound of the formula ##STR7##in which X₈ and X₉ represent radicals which can be split off with theformation of the carbonyl group which, in the compounds of the formulaI, is bonded to R₃ and the nitrogen atom, or from a salt thereof, withthe formation of the carbonyl group and, if desired, the additionalprocess steps are carried out.

The starting material of the formula IX in the form of an acid additionsalt is, for example, the acid addition salt with a mineral acid.

Usually, one of the radicals X₈ and X₉ represents hydrogen, whilst theother denotes the acyl radical of a carbonic acid derivative, such as ofa corresponding ester, halide or amide, and represents, for example,lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, orhalogenocarbonyl, such as chlorocarbonyl or aminocarbonyl.

The reaction is carried out in the absence or presence of a suitablesolvent or diluent, such as an optionally substituted, for examplechlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such asbenzene, and, if necessary, with cooling or warming, for example in atemperature range of from about 0° to about 100°, in a closed vesseland/or in an inert gas atmosphere, for example a nitrogen atmosphere.Optionally, and if one of the radicals X₈ or X₉ denotes aminocarbonylpreferably, the reaction is carried out in the presence of a basiccondensing agent, say of a metal alcoholate, such as an alkali metalalcoholate, for example sodium ethylate, in a solvent, say in a loweralkanol, such as ethanol. The reaction is appropriately carried out in atemperature range of about 0°-150° and preferably of 10°-120°.

Starting materials of the formula IX can be manufactured in a mannerwhich is in itself known and optionally in situ. Thus, preferredstarting materials can be obtained when, for example, the phenolichydroxy group in 2,3-dinitrophenol is converted, such as by treatmentwith an allyl halide, for example allyl bromide, in the presence of abase, for example potassium carbonate, into the allyloxy group, this isconverted, by treating the intermediate product with hydrogen peroxide,for example in the presence of potassium bicarbonate, or with a suitableinorganic or organic percarboxylic acid, for example 3-chloro-perbenzoicacid, into the 2,3-epoxy-propoxy group and the latter is converted, forexample by treating the intermediate product with an amine of theformula R₁ -NH₂ (IIIa) into the 3-(R₁ -amino)-2-hydroxy-propoxy group.The two nitro groups in a 3-[3-(R₁-amino)-2-hydroxy-propoxy]-1,2-dinitrobenzene which is thus obtainableare then reduced to the amino groups, for example by treatment withcatalytically activated hydrogen. Reaction with a suitable reactivederivative of carbonic acid, for example a corresponding ester, such asa di-lower alkyl carbonate, for example dimethyl carbonate or diethylcarbonate, a mixed anhydride, such as a carbonic acid dihalide, forexample phosgene, or an amide, for example urea orN,N'-carbonyl-diimidazole, gives a preferred starting material, which ispreferably formed only in situ and is converted direct into a compoundof the formula I.

The new compounds of the formula I wherein R₂ represents hydrogen canalso be obtained by reducing in a compound of the formula ##STR8##wherein X₁₀ represents one of the radicals of the formula R₁--NH--(C═X₁₁)--(Xa) or R₄ --(C═X₁₁)--NH--CH₂ --(Xb), in which R₄corresponds to the radical R₁ containing one methylene group less, andX₁₁ represents the oxo or thioxo group, the group of the formula X₁₀,optionally by way of the intermediates containing the radical of theformula ##STR9## wherein X₄ represents a radical having the abovemeaning and which can be split off by hydrogenolysis or by reduction, togive the radical of the formula

    R.sub.1 --NH--CH.sub.2 --                                  (XII);

and, if desired, carrying out the additional stages of the process.Particularly suitable reducing agents for reducing the groups Xa and Xb,and for reducing the corresponding groups of the formula ##STR10## whichcontain a carbamoyl grouping, are light-metal hydrides, such as alkalimetal aluminium hydrides, e.g. lithium aluminium hydride (which aresuitable in particular for reducing carbamoyl groups), or alkali metalborohydrides, e.g. sodium cyanoborohydrides, or borohydrides, e.g.diborane.

Groupings of the formulae (Xa) and (Xb) in which X₁₁ represents in eachcase a thioxo group, and which optionally contain a radical R₄ which canbe split off by hydrogenolysis, are converted by reductivedesulphurisation, e.g. by treatment with a hydrogenating catalyst suchas Raney nickel, into the grouping of the formula (XII).

The above reducing reactions are performed in a manner known per se,usually in the presence of an inert solvent and, if necessary, withcooling or heating, e.g. in a temperature range of about -20° C. toabout +150° C., and/or in a closed vessel under pressure, and/or in aninert-gas atmosphere, e.g. in a nitrogen atmosphere.

Starting materials of the formula (X) can be obtained by reaction ofamino compounds of the formula ##STR11## with carboxylic acid compoundsof the formula ##STR12## wherein R₄ has the aforementioned meaning, orwith reactive derivatives thereof, such as the halides, e.g. chloridesor lower alkyl esters, e.g. methyl esters; or by reaction of aminocompounds of the formula

    R.sub.1 --NH.sub.2                                         (XVI)

with carboxylic acid compounds of the formula ##STR13## or with reactivederivatives thereof, e.g. as defined under formula (XV), wherein thehydroxyl group can optionally be in a protected form, e.g. in anesterified or suitable etherified form. In an intermediate with aprotected hydroxyl group, this is converted into the free form. Theabove reactions are performed in a manner known per se.

Starting materials of the formula (XIII) can be obtained, e.g., byreacting a compound of the formula (II), wherein X₁ and X₂ togetherrepresent the epoxy group, with ammonia or with an α-arylamine, e.g.benzylamine, and subsequently splitting off the α-aryl radical, forinstance the benzyl radical, by reduction; or by reacting a compound ofthe formula (II) wherein X₂ represents the hydroxyl group and X₁represents halogen, e.g. chlorine, with hexamethylenetetramine, andsubsequently decomposing the resulting product with dilute mineral acid,e.g. with dilute hydrochloric acid. These reactions are performed in amanner known per se.

Within the scope of the definition of the compounds of the formula I,compounds obtained according to the process can be converted in thecustomary manner into other end products.

Thus, in compounds of the formula I in which R₂ represents hydrogen thelatter can be replaced by lower alkanoyl in a manner which is in itselfknown, for example by treating the corresponding compound of the formulaI, or preferably a salt, such as a mineral acid addition salt, thereof,with a lower alkanecarboxylic acid or a reactive derivative, such as ananhydride, optionally a mixed anhydride, thereof, for example a halide,such as the chloride, thereof. In this reaction, a ring nitrogen atomcan optionally also be acylated; a lower alkanoyl group introduced inthis way can be split off selectively, for example by hydrolysis.

Furthermore, in a compound of the formula I in which R₂ represents loweralkanoyl, the latter can be split off by solvolysis, for example bymeans of hydrolysis, and replaced by hydrogen.

Depending on the process conditions and the starting materials, the newcompounds are obtained in the free form or in the form of their salts,which is also included in the invention, and the new compounds or saltsthereof can also be in the form of hemihydrates, monohydrates,sesquihydrates or polyhydrates. Salts of the new compounds can beconverted into the free compounds in the manner which is in itselfknown, acid addition salts for example, by treatment with basic agents,such as alkali metal hydroxides, carbonates or bicarbonates, or ionexchangers, and metal salts, such as alkali metal salts, which areoptionally obtainable according to the process, for example by treatmentwith acid agents, such as a mineral acid. On the other hand, resultingfree compounds can form acid addition salts in a manner which is initself known, for example by treatment with organic or inorganic acids,such as the abovementioned acids, and the acids used for the manufactureare in particular those acids which are suitable for the formation ofsalts which can be used pharmaceutically.

These, or other salts, especially acid addition salts of the newcompounds, such as, for example picrates or perchlorates, can also beused to purify the resulting free bases, the free compounds beingconverted into salts, these being separated off and purified and thefree compounds being reformed from the salts.

Depending on the choice of the starting materials and procedures, thenew compounds can be in the form of optical antipodes or racemates.

Resulting racemates can be resolved into the antipodes according tomethods which are in themselves known, for example by recrystallisationfrom an optically active solvent, by treatment with suitablemicro-organisms or by reaction with an optically active compound whichforms a salt with the racemic compound, especially a corresponding acid,and separation of the salt mixture obtained in this way, for example onthe basis of different solubilities, into the diastereomeric salts, fromwhich the free antipodes can be liberated by the action of suitableagents. Optically active acids which are particularly commonly used are,for example, the D and L forms of tartaric acid, di-o-toluyltartaricacid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid,aspartic acid or quinic acid. Advantageously, the more active of the twoantipodes is isolated.

The invention also relates to those embodiments of the process accordingto which a compound obtainable as an intermediate product at any stageof the process is used as the starting material and the missing processsteps are carried out, or the process is discontinued at any stage, orin which a starting material is formed under the reaction conditions, orin which a reactant is optionally present in the form of its salts.

Appropriately, the starting materials used for carrying out thereactions according to the invention are those which lead to the groupsof end products mentioned in particular initially and especially to theend products which have been described or singled out specifically.

The new compounds can be used, for example, in the form ofpharmaceutical formulations which contain a pharmacologically effectiveamount of the active substance, optionally together with inorganic ororganic, solid or liquid, excipients which can be used pharmaceuticallyand are suitable for enteral, for example oral, or parenteraladministration. Thus, tablets or gelatine capsules are used whichcontain the active compound together with diluents, for example lactose,dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and/orlubricants, for example silica, talc, stearic acid or salts thereof,such as magnesium stearate or calcium stearate, and/or polyethyleneglycol. Tablets can also contain binders, for example magnesiumaluminium silicate, starches, such as corn starch, wheat starch, ricestarch or arrowroot, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone and, if desired,disintegrating agents, for example starches, agar, alginic acid or asalt thereof, such as sodium alginate, and/or effervescent mixtures, oradsorbents, dyestuffs, flavouring substances and sweeteners.Furthermore, the new pharmacologically active compounds can be used inthe form of formulations which can be administered parenterally, or ofinfusion solutions. Such solutions are, preferably, isotonic aqueoussolutions or suspensions and these can, for example, be manufacturedbefore use from lyophilised formulations which contain the activecompound by itself or together with an excipient, for example mannitol.The pharmaceutical formulations can be sterilised and/or containauxiliaries, for example preservatives, stabilisers, wetting agentsand/or emulsifiers, solubilising agents, salts for regulating theosmotic pressure and/or buffers. The present pharmaceutical formulationswhich can, if desired, contain further pharmacologically activesubstances, are manufactured in a manner which is in itself known, forexample by means of conventional mixing, granulating, dragee-making,dissolving or lyophilising processes, and contain from about 0.1% to100%, and especially from about 1% to about 50%, of the active compoundand lyophilisates contain up to 100% of the active compound.

The dosage can depend on various factors, such as the mode ofadministration and the species, age and/or state of the individual. Inthe case of oral administration, the doses to be administered daily arebetween about 1 mg and about 15 mg for warm-blooded animals weighingabout 70 kg.

The examples which follow serve to illustrate the invention; thetemperature are given in degrees Centigrade.

EXAMPLE 1

A mixture of 3.3 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one in 80 mlof isopropanol and 8.8 g of tert.-butylamine is heated to the boil underreflux for 2 hours. The solvent, together with the excess amine, is thendistilled off under reduced pressure. The residual oil which contains4-(3-tert.-butylamino-2-hydroxy-propoxy)-benzimidazol-2-one is dried at50°/0.01 mm Hg for 2 hours and dissolved in 30 ml of acetone. 2.5 ml ofa 5 N solution of hydrogen chloride in diethyl ether is added to thesolution. The crystalline precipitate is recrystallised from a mixtureof methanol and acetone. This gives4-(3-tert.-butylamino-2-hydroxy-propoxy)-benzimidazol-2-onehydrochloride in the form of colourless crystals which melt at 250°-260°with gradual decomposition.

The starting material can be prepared as follows: 225 g of potassiumcarbonate and 98 g of allyl bromide are added to a solution of 170.0 gof dimethyl 3-hydroxy-phthalate in 400 ml of methyl ethyl ketone. Themixture is heated to the reflux temperature for 18 hours, whilststirring, and then filtered, the filter residue is washed with methylethyl ketone and the filtrate, combined with the wash liquid, isevaporated under reduced pressure. The residual oily crude product isdistilled under reduced pressure; dimethyl 3-allyloxyphthalate isobtained as the main fraction; boiling point 126°-130°/0.015 mm Hg.

A mixture of 68.5 g of dimethyl 3-allyloxy-phthalate and 154 ml of a 5 Naqueous solution of sodium hydroxide is heated to the reflux temperaturefor 3 hours, whilst stirring, and then cooled to a temperature of +10°.129 ml of 6 N hydrochloric acid are added in portions to the clearreaction solution and during the addition the temperature is not allowedto rise above 20°. After standing for several hours at 0°, thecrystalline precipitate is filtered off and washed with a little icewater. After drying at 50°/0.1 mm Hg to constant weight,3-allyloxy-phthalic acid is obtained; melting point 166°-167°.

A mixture of 45.8 g of 3-allyloxy-phthalic acid in 200 ml of toluene and25.5 ml of acetic anhydride is heated to the reflux temperature for 3hours and then evaporated under reduced pressure. The residue iscrystallised from diethyl ether and gives 3-allyloxy-phthalic anhydride;melting point 115°-117°.

26 ml of trimethylsilyl azide are added to a suspension of 14.4 g of3-allyloxy-phthalic anhydride in 100 ml of absolute benzene and themixture is slowly heated to the boil, whilst stirring, whereupon avigorous evolution of nitrogen starts. After the reaction has subsided,the mixture is heated to the boil for a further 2 hours, the solvent isthen removed under reduced pressure and the residue is dissolved in 50ml of ethanol and 5 ml of water. The solution is heated to the boil for18 hours under reflux and then evaporated under reduced pressure. Theresulting residue is ground with diethyl ether, whereuponcrystallisation takes place. The crystalline product is filtered off,washed with diethyl ether, dried in air and, for further purification,extracted with 100 ml of hot water. The crystals which are insoluble inwater are 4-allyloxy-benzimidazol-2-one; melting point 192-193.

2.0 g of benzonitrile, 5 ml of 30% strength aqueous hydrogen peroxideand 0.3 g of potassium bicarbonate are added to a solution of 2.8 g of4-allyloxy-benzimidazol-2-one in 50 ml of methanol. After stirring for44 hours at 20°, a crystalline precipitate forms; the reaction mixtureis left to stand for one hour at 0° and then filtered. The filterresidue is washed with a little cold methanol and then with diethylether; 4-(2,3-epoxy-propoxy)-benzimidazol-2-one, which is thusobtainable, melts at 143°-144°.

EXAMPLE 2

After adding 15.2 g of tert.-butylamine, a mixture of 4.6 g of8-(2,3-epoxy-propoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one in 150 mlof isopropanol is heated to the boil under reflux for 2 hours. Thesolvent, together with the excess volatile amine, is then distilled offunder reduced pressure. The residue, which contains8-(3-tert.-butylamino-2-hydroxypropoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one,is dried at 50°/0.01 mm Hg for 2 hours and then dissolved in methanoland 5 ml of a 5 N solution of hydrogen chloride in diethyl ether areadded to the solution. The mixture is evaporated to dryness, acetone isadded and8-(3-tert.-butylamino-2-hydroxypropoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-onehydrochloride is thus obtained as a colourless crystalline product;melting point 182°-183° after recrystallisation from a mixture ofmethanol and acetone.

The starting material can be prepared as follows:

0.030 g of p-toluenesulphonic acid and 17.8 g of 3,4-dihydro-2H-pyraneare added to a mixture of 29.8 g of 2,3-dihydroxy-nitrobenzene in 400 mlof absolute benzene and the solution is left to stand for 7 days at 20°.It is filtered through 15 g of a silica gel formulation (Merck silicagel 60; grain size 0.063-0.200 mm) and the silica gel is rinsed withbenzene. After distilling off the benzene under reduced pressure, areddish oil is obtained which, when crystallised from hexane, gives2-hydroxy-3-(tetrahydropyran2-yloxy)-nitrobenzene in the form of yellowcrystals; melting point 72°-73°.

A mixture of 38.4 g of2-hydroxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene, 22.2 g of potassiumcarbonate and 27.0 g of ethyl bromoacetate in 400 ml of methyl ethylketone is heated to the reflux temperature for 16 hours, whilststirring, and then filtered; the filter residue is rinsed with 100 ml ofmethyl ethyl ketone. The combined filtrates are evaporated under reducedpressure. The residual yellowish oil is taken up in 400 ml of diethylether, the solution is clarified by filtration, with the addition of 2 gof an active charcoal formulation and the filtrate is evaporated underreduced pressure. The residual oil solidifies after some time to give amass of crystals and gives2-ethoxycarbonylmethoxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene;melting point 65°-66°.

108 ml of 2 N hydrochloric acid are added to a solution of 48.5 g of2-ethoxycarbonylmethoxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene in 972ml of methanol at 20°. After 1 hour, 216 ml of a 1 N aqueous solution ofsodium bicarbonate are added dropwise, whilst stirring. The methanol isdistilled off under reduced pressure and3-nitro-2-ethoxycarbonylmethoxy-phenol crystallises out and is filteredoff, washed with water and dried over calcium sulphate under reducedpressure; melting point 49°-50°.

A mixture of 31.7 g of 3-nitro-2-ethoxycarbonylmethoxyphenol, 18.1 g ofpotassium carbonate and 17.2 g of allyl bromide in 400 ml of methylethyl ketone is heated to the reflux temperature for 16 hours, whilststirring. The mixture is filtered, the filter residue is rinsed with 100ml of methyl ethyl ketone and the filtrate, together with the washliquid, is evaporated under reduced pressure. The yellowish oil consistsof 2-ethoxycarbonylmethoxy-3-allyloxy nitrobenzene and is furtherprocessed without purification.

A solution of 28.7 g of 2-ethoxycarbonylmethoxy-3-allyloxy-nitrobenzenein 185 ml of glacial acetic acid is warmed to 90°, whilst stirring, anda total of 31 g of iron filings (corroded slightly with hydrochloricacid, and then dried, before use; compare Houben-Weyl, volume 11/1, page397) and 90 ml of water are then added alternately in portions. Themixture is stirred for a further 1 hour at 90° and filtered, the filterresidue is washed with methylene chloride and the filtrate, togetherwith the wash liquid, is evaporated under reduced pressure. The residueis partitioned between ethyl acetate and water; the organic phase iswashed with water and a 4 N aqueous solution of sodium carbonate,separated off, dried over sodium sulphate and evaporated under reducedpressure. The crystalline residue is recrystallised from ethanol andgives 8-allyloxy-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one in the form ofcolourless crystals; melting point 174°-175°.

5.2 g of benzonitrile, 18 ml of a 30 percent strength aqueous solutionof hydrogen peroxide and 1.0 g of potassium bicarbonate are added to asuspension of 10.1 g of 8-allyloxy2,3-dihydro-(4H)-benz[5.6]oxazin-3-onein 400 ml of methanol and the mixture is then stirred for 3 days at 20°.The reaction mixture is then concentrated to a volume of 40 ml underreduced pressure. After leaving to stand at 0°,8-(2,3-epoxy-propoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one is obtainedin the form of colourless crystals, which are filtered off and washedwith a little cold methanol; melting point 158°-160°.

EXAMPLE 3

Tablets containing 0.002 g of4-(3-tert.-butylamino-2-hydroxy-propoxy)-benzimidazol-2-onehydrochloride are manufactured as follows:

    ______________________________________                                        Composition (for 1,000 tablets):                                              ______________________________________                                        4-(3-tert.-Butylamino-2-hydroxy-propoxy)-                                     benzimidazol-2-one hydrochloride                                                                        2.00   g                                            Lactose                   35.00  g                                            Maize starch              50.00  g                                            Colloidal silica          6.00   g                                            Talc                      6.00   g                                            Magnesium stearate        1.00   g                                            Water, q.s.                                                                   ______________________________________                                    

The 4-(3-tert.-butylamino-2-hydroxy-propoxy)-benzimidazol-2-onehydrochloride is mixed with the lactose, part of the maize starch andwith colloidal silica and the mixture is forced through a sieve. Afurther part of the maize starch is mixed to a paste with five times theamount of water on a waterbath and the powder mixture is kneaded withthis paste until a slightly plastic mass has formed. This is pressedthrough a sieve with a mesh width of about 3 mm and dried and the drygranules are again forced through a sieve. The remaining maize starch,the talc and the magnesium stearate are then mixed in and the resultingmixture is pressed to give tablets weighing 0.100 g (with a breakinggroove).

In an analogous manner, other compounds of the formula I, or theirsalts, such as, for example8-(3-tert.-butylamino-2-hydroxy-propoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one,5-(3-tert.-butylamino-2-hydroxy-propoxy)-3,4-dihydro-1H-quinazolin-2-one,7-(3-tert.-butylamino-2-hydroxy-propoxy)-2(3H)-benzoxazolone,4-(3-tert.-butylamino-2-hydroxy-propoxy)-3-methyl-benzimidazol-2-one,4-[3-(1-phenyl-propyl-2-amino)-2-hydroxy-propoxy]-benzimidazol-2-one,4-[3-(2-(3,4-dimethoxyphenyl)-ethylamino)-2-hydroxy-propoxy]-benzimidazol-2-one,4-[3-(2-(3,4-methylenedioxphenyl)-ethylamino)-2-hydroxypropoxy]-benzimidazol-2-one,4-[3-[2-(4-hydroxyphenyl)-ethylamino]-2-hydroxy-propoxy]-benzimidazol-2-one,4-[3-[2-(2-hydroxyphenoxy)-ethylamino]-2-hydroxy-propoxy]-benzimidazol-2-oneand8-[3-[2-(3,4-dimethoxyphenyl)-ethylamino]-2-hydroxy-propoxy]-benzo[3,2-a]-1,4-oxazin-3(4H)-oneor their salts, especially their non toxic acid addition salts, whichcan be used pharmaceutically, can be used as active compounds in thetablets described.

EXAMPLE 4

After adding 1 g of palladium-on-charcoal catalyst, a solution of 10.9 gof5-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-3,4-dihydro-1H-quinazolin-2-onein 220 ml of dimethylformamide is hydrogenated under normal conditionsuntil the absorption of hydrogen has ceased. After filtering andevaporating the filtrate, crude crystals of5-(3-tert.-butylamino-2-hydroxy-propoxy)-3,4-dihydro-1H-quinazolin2-onewith a melting point of 204°-205° are obtained. After passing 1equivalent of hydrogen chloride into a solution of the compound in amixture of 150 ml of isopropanol and 50 ml of methanol, thehydrochloride, which as a melting point of 274°-275°, is obtained.

The starting material can be prepared as follows:

(a) A solution of 336 g of 1,3-dinitrobenzene and 174 g of allyl alcoholin 2,000 ml of dioxane is warmed to 40° and a solution of 196 g ofpotassium cyanide in 400 ml of water is added in the course of about 10minutes. During the addition the temperature rises to about 60°. Thereaction mixture is stirred at 80° for 2 hours, cooled to about 10° andfiltered through diatomaceous earth and the filtrate is evaporated. Theevaporation residue is dissolved in 2 liters of ethyl acetate and thesolution is washed with 5 times 1 liter of water. The dark organic phaseis clarified with active charcoal and silica gel. After evaporating offthe solvent, a dark red, partially crystalline residue remains and, bycrystallisation from isopropanol, this gives2-allyloxy-6-nitro-benzonitrile with a melting point of 102°-104°. Afurther amount of the same compound is obtained by chromatography on 2kg of silica gel and elution with toluene. (Fractions 17-35 with 1 literof toluene).

(b) 22.5 g of 2-allyloxy-6-nitro-benzonitrile are introduced into asolution of 26.8 g of m-chloroperbenzoic acid (85% strength) in 1 literof chloroform and the mixture is warmed to 50° in the course of 3 hours.The reaction mixture is kept at this temperature for 24 hours and thencooled and the solution is washed with 100 ml of 1 M sodium sulphitesolution, then with 100 ml of 2 N sodium hydroxide solution and finallywith 100 ml of water. After drying over magnesium sulphate andevaporating the solution, a colourless crystalline residue is obtainedand this is ground with 20 ml of isopropanol, the mixture is filteredand the material on the filter is dried in vacuo, after which crude2-(2,3-epoxypropoxy)-6-nitro-benzonitrile with a melting point of131°-135° is obtained and this is used further in the form of the crudeproduct.

(c) A suspension of 23.4 g of 2-(2,3-epoxy-propoxy)6-nitro-benzonitrileand 34.6 g of N-benzyl-tert.-butylamine in 550 ml of isopropanol iswarmed under reflux until a solution forms and this is then heated underreflux for a further 8-10 hours. On cooling,1-(N-benzyl-tert.-butylamino)-3-(2-cyano-3-nitro-phenoxy)-2-propanolwith a melting point of 120°-122° crystallises out; a further amount ofthis compound is obtained by concentrating the filtrate.

(d) 28.0 g of1-(N-benzyl-tert.-butylamino)-3-(2-cyano-3-nitro-phenoxy)-2-propanol aredissolved in 350 ml of ethanol in a flask provided with a stirrer, areflux condenser and a dropping funnel, by heating to the boil. Afteradding about 0.5 ml of a suspension of Raney nickel, a solution of 18.2g of hydrazine hydrate in 20 ml of ethanol is added dropwise, whilst themixture is boiling, at such a rate that vigorous evolution of gasstarts. After the addition is complete, the mixture is heated to theboil for a further half hour. The reaction mixture is then cooled andfiltered through diatomaceous earth and the filtrate is evaporated. Theresidual oil is crude6-[2-hydroxy-3-(N-benzyl-tert.-butylamino)-propoxy]-anthranilamide andis further processed without further purification.

(e) A solution of 27 g of6-[2-hydroxy-3-(N-benzyltert.-butylamino)-propoxy]-anthranilamide in 400ml of tetrahydrofurane is added dropwise, under nitrogen, to asuspension of 8.3 g of lithium aluminium hydride in 100 ml oftetrahydrofurane. After stirring for 20 hours under reflux, a further8.0 g of lithium aluminium hydride are added and the mixture is againheated to the boil for 60°-65 hours. Whilst cooling with ice, the excesslithium aluminium hydride is decomposed by means of 17 ml ofconcentrated sodium hydroxide solution and 40 ml of water. Theprecipitate is filtered off and washed with 50 ml of tetrahydrofuraneand the combined filtrates are evaporated. This gives crude2-aminomethyl-3-[2-hydroxy-3-(N-benzyl-tert.-butylamino)-propoxy]-anilinein the form of an oil which, on dissolving in methanol and passinghydrogen chloride into the solution until it gives an acid reaction,gives the hydrochloride which has a melting point of 260°-265°.

(f) 5.3 g of methyl chloroformate are added dropwise to a solution of16.2 g of2-aminomethyl-3-[2-hydroxy-3-(N-benzyl-tert.-butylamino)-propoxy]-anilinein a mixture of 150 ml of isopropanol and 150 ml of water, at 15°-20°,whilst stirring and cooling with ice. The reaction mixture is stirred atroom temperature for a further 2 hours and then evaporated. The residueis dissolved in 100 ml of water, the solution is extracted with 50 ml ofether and the aqueous phase is rendered alkaline with concentratedammonia and extracted 3 times with, in each case, 200 ml of ethylacetate. The residue which remains after evaporating the organic phaseis dissolved in 50 ml of methanol and boiled with 4.86 g of sodiummethylate under reflux for 3 hours. The crystalline precipitate whichgradually forms is filtered off after cooling the reaction mixture in anice bath, whereupon5-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-3,4-dihydro-1H-quinazolin-2-onewith a melting point of 215°-217° is obtained.

EXAMPLE 5

Analogously to Example 4(f), 8.0 g of2-aminomethyl-3-(3-tert.-butylamino-2-hydroxy-propoxy)-aniline arereacted first with 3.3 g of methyl chloroformate in a mixture of 28 mlof isopropanol and 28 ml of water and then with 3.2 g of sodiummethylate in 30 ml of methanol. After working up,5-(3-tert.-butylamino-2-hydroxy-propoxy)-3,4-dihydro-1H-quinazolin-2-onewith a melting point of 204°-205° is obtained.

The starting material can be prepared in the following way:

(a) A mixture of 11.0 g of the 2-(2,3-epoxypropoxy)-6-nitro-benzonitrileobtained according to Example 4(b) and 18.5 g of tert.-butylamine in 300ml of isopropanol is heated under reflux for 5-6 hours. Afterevaporating, a crystalline residue remains and this is stirred with 20ml of carbon tetrachloride and the mixture is then filtered, whereupon1-tert.-butylamino-3-(2-cyano-3-nitro-phenoxy)-2-propanol with a meltingpoint of 115°-118° is obtained.

(b) 12.2 g of 1-tert.-butylamino-3-(2-cyano-3-nitrophenoxy)-2-propanolare reacted in 200 ml of ethanol with 11 g of hydrazine hydrate andRaney nickel, analogously to Example 4(d), and after filtering andevaporating the filtrate, this gives crude6-(3-tert.-butylamino-2-hydroxy-propoxy)-anthranilamide in the form ofan oil which is used further without further purification.

(c) 12 g of crude 6-(3-tert.-butylamino-2-hydroxypropoxy)-anthranilamideare dissolved in 400 ml of tetrahydrofurane and reduced, analogously toExample 4(e), with 6.1 g of lithium aluminium hydride for 48 hours.After working up,2-aminomethyl-3-(3-tert.-butylamino-2-hydroxy-propoxy)-aniline isobtained in the form of an oil which is further used as such. It forms atri-hydrochloride with a melting point of 250°-260° (with sublimation).

EXAMPLE 6

After adding 1 g of palladium-on-charcoal catalyst (5% strength), asolution of 7.0 g of5-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-(1H)(3H)-quinazoline-2,4-dionein 200 ml of 2-methoxy-ethanol is hydrogenated under normal conditionsuntil the calculated amount of hydrogen has been taken up. Afterfiltering and evaporating the solvents, a crystalline residue means andthis is stirred with 10 ml of isopropanol and the mixture is thenfiltered, whereupon5-(3-tert.-butylamino-2-hydroxy-propoxy)-(1H)(3H)-quinazoline-2,4-dionewith a melting point of 271°-275° is obtained. The hydrochloride meltsat 298°-305° (with decomposition).

The starting material can be prepared in the following way:

(a) 16 g of the crude6-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-anthranilamideobtained according to Example 4(d) are dissolved in 45 ml of glacialacetic acid and a solution of 7.45 g of potassium cyanate in 23 ml ofwater is added. Due to the exothermic reaction which starts, theinternal temperature of the reaction mixture rises to 41°. The solutionis stirred for a further 4 hours at room temperature and poured into 200ml of water and the mixture is rendered alkaline with 2 N sodiumcarbonate solution. The crystals of2-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-6-ureidobenzamidewhich have precipitated out are filtered off and recrystallised from alittle isopropanol; melting point (158°), 163°-167°.

(b) 9.7 g of2-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-6-ureido-benzamideare added to a solution of 0.65 g of sodium in 100 ml of absoluteethanol and the suspension is heated under reflux and whilst stirringuntil no further elimination of ammonia can be observed (about 5-6hours) The suspension is cooled and the crystals are filtered off andwashed with 20 ml of ethanol and then with 20 ml of water. After dryingin vacuo at 90° for 14 hours, the5-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-(1H)(3H)-quinazoline-2,4-dionewhich is thus obtained melts at 190°-192°.

EXAMPLE 7

3.24 g of 2-(3-tert.-butylamino-2-hydroxy-propoxy)-6-ureido-benzamideare boiled with a solution of 0.28 g of sodium in 150 ml of absoluteethanol for 1.5 hours under reflux, the reaction mixture is evaporatedand the residue is dissolved in 50 ml of water. After neutralising theaqueous solution with 2 N hydrochloric acid, the mixture is filtered,the filtrate is evaporated and the residue is extracted by boiling with100 ml of methanol. The undissolved material is filtered off and thefiltrate is evaporated, whereupon5-(3-tert.-butylamino-2-hydroxy-propoxy)-(1H)(3H)-quinazoline-2,4-dioneis obtained in the form of the hydrochloride with a melting point of298°-305° (with decomposition).

The starting material can be prepared in the following way:

(a) 6.2 g of the2-[3-(N-benzyl-tert.-butylamino)-2-hydroxy-propoxy]-6-ureido-benzamideobtained according to Example (6a) are hydrogenated in 500 ml ofmethanol in the presence of 0.6 g of palladium-on-charcoal catalyst (5%strength) until the absorption of hydrogen has ceased.2-[3-tert.-Butylamino-2-hydroxy-propoxy]-6-ureido-benzamide with amelting point of 189°-191° is obtained by filtering the mixture,evaporating the filtrate and adding isopropanol to the residue.

EXAMPLE 8

3.7 g of7-[3-(N-benzyl-tert.-butylamino)-2-hydroxypropoxy-]-2-(3H)-benzoxaloneare hydrogenated under normal conditions in 70 ml of methanol with theaddition of 0.4 g of palladium-on-charcoal catalyst until the absorptionof hydrogen has ceased. After filtering off the catalyst, the filtrateis neutralised with a 5 N solution of hydrogen chloride in ethanol andevaporated and the residual oil is made to crystallise with acetone.This gives 7-(3-tert.-butylamino-2-hydroxy-propoxy)-2(3H)-benzoxazolonehydrochloride, which after recrystallisation from methanol/acetone meltsat 221°-224°.

The starting material can be prepared as follows:

(a) 125 g of finely powdered, dried silver nitrate are added in portionsto a solution of 140 g of o-allyloxyphenyl acetate and 100 ml of acetylchloride in 300 ml of freshly distilled carbon tetrachloride, at -5° to-15°, whilst stirring and cooling with an ice/sodium chloride bath. Thetemperature of the reaction mixture is allowed to rise gradually to 20°in the course of 3 hours, the mixture is filtered and the filtrate iswashed with a saturated solution of urea in water and evaporated. Thisgives a light brown oily residue which is chromatographed in 250 mlfractions over 800 g of silica gel using toluene. Fractions 1-4 arediscarded. The component which boils at 125°-135°/0.1 mm Hg and isphenyl 2-allyloxy-3-nitro-acetate is isolated from fractions 5 and 6 and7-11.

(b) 31.0 g of the compound obtained according to (a) are dissolved in200 ml of ethanol, 40 ml of a 10 N solution of hydrogen chloride inethanol are added and the mixture is heated to the boil under reflux for2 hours. After evaporating the solution, washing the residue with waterand distilling under 0.06 mm Hg, 2-allyloxy-3-nitrophenol which boils at90°-103°/0.06 mm Hg is obtained.

(c) 10.0 g of 2-allyloxy-3-nitrophenol, 27 g of potassium carbonate and54 ml of epichlorohydrin in 300 ml of acetone are stirred under refluxfor 15-20 hours. After filtering the reaction mixture and evaporatingthe filtrate, crude 2-allyloxy-1-(2,3-epoxy-propoxy)-3-nitrobenzene isobtained and this can be used further as such.

(d) 14 g of crude 2-allyloxy-1-(2,3-epoxy-propoxy)-3-nitrobenzen and11.0 g of N-benzyl-tert.-butylamine in 70 ml of isopropanol are boiledunder reflux for 7 hours. After neutralising with concentratedhydrochloric acid,1-[2-allyloxy-3-nitro-phenoxy]-3-(N-benzyl-tert.-butylamino)-2-propanolcrystallises out in the form of the hydrochloride and afterrecrystallisation from methanol/isopropanol this melts at 206°-209° withthe evolution of gas. The base is an oil.

(e) A solution of 19.4 g of1-(2-allyloxy-3-nitro-phenoxy)-3-(N-benzyl-tert.-butylamino)-2-propanolin a mixture of 350 ml of ethanol, 35 ml of water and 5 ml oftriethylamine, with the addition of 1 g of rhodiumtris-(triphenylphosphine)chloride, is stirred under reflux for 45minutes. After filtering and evaporating the filtrate, crude1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-nitro-phenoxy)-2-propanolis obtained in the form of a dark red oil, which is used further withoutfurther purification.

(f) A solution of 16.1 g of crude1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-nitro-phenoxy)-2-propanolin 150 ml of ethanol is reduced, analogously to Example (4d), with 15 mlof hydrazine hydrate and Raney nickel to give1-(N-benzyl-tert.-butylamino)-3-(3-amino-2-hydroxy-phenoxy)-2-propanol.The base forms a dark oil which is used further without furtherpurification. The base crystallises from ether as greenish crystals witha melting point of 105°-110°.

(g) 14.5 g of1-(N-benzyl-tert.-butylamino)-3-(3-amino-2-hydroxy-phenoxy)-2-propanolare dissolved in 140 ml of an isopropanol/water mixture (1:1) and 5.0 mlof methyl chloroformate are added, at 15°-20°, whilst stirringvigorously and stirring is continued for a further 11/2 hours at roomtemperature, the reaction mixture is then evaporated and the residue isdissolved in 50 ml of water. After extraction with 20 ml of ethylacetate, the acid aqueous phase is rendered alkaline with concentratedsodium hydroxide solution and extracted with 3 times 100 ml of methylenechloride. Evaporation of the organic phase gives the crude base, fromwhich crystalline1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-methoxycarbonylamino-phenoxy)-2-propanolwith a melting point of 130°-133° is isolated.

(h) 6.4 g of1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-methoxycarbonylamino-phenoxy)-2-propanolare introduced in portions, at 10°-15°, into an ice-cooled suspension of1.0 g of a 50% strength dispersion of sodium hydride in1,2-dimethoxyethane and the mixture is heated under reflux for 1 hour.The reaction mixture is evaporated and the residue is partitionedbetween 1.5 ml of glacial acetic acid, 10 ml of water and 100 ml ofethyl acetate. The aqueous phase is again extracted with 100 ml of ethylacetate. After evaporation, the combined ethyl acetate extracts give acrude base which is purified via the neutral fumarate which has amelting point of 202°-206°.

EXAMPLE 9

A mixture of 2.6 g of 7-(2,3-epoxy-propoxy)-4H-1,3-benzoxazin-2(1H)-one,75 ml of isopropanol and 7.6 g of tert.-butylamine is reactedanalogously to Example 2. After working up, the residue isrecrystallised from a mixture of methanol and acetone, whereupon7-(3-tert.-butylamino-2-hydroxypropoxy)-4-H-1,3-benzoxazin-2(1H)-onehydrochloride with a melting point of 243°-244° is obtained.

The starting material can be prepared as follows:

(a) 3.14 ml of boron tribromide are added to a solution of 24.6 g of2-nitro-6-methoxybenzyl bromide in 50 ml of methylene chloride at 0° andthe reaction mixture is then left to stand for one hour at 20° and isthen stirred for 20 hours under reflux. The reaction mixture is thenevaporated under reduced pressure, the residue is dissolved in 100 ml ofglacial acetic acid, 40 g of anhydrous sodium acetate are added and themixture is heated to the boil for 10 minutes, whilst stirring. Themixture is then poured into 500 ml of ice water and extracted threetimes with ether. The ether extract is washed with aqueous sodiumbicarbonate solution, dried over sodium sulphate and evaporated. Ongrinding with hexane, the oily residue gives 2-nitro-6-hydroxybenzylacetate; melting point 113°-114°.

(b) A mixture of 24.9 g of 2-nitro-6-hydroxybenzyl acetate, 150 ml ofmethyl ethyl ketone, 11.4 ml of allyl bromide and 18.1 g of potassiumcarbonate is stirred under reflux for 5 hours. After cooling, theinorganic salts are filtered off, the residue is rinsed with methylethyl ketone and the filtrate is evaporated under reduced pressure. Theresidual oil is dissolved in benzene and the solution is chromatographedover 300 g of silica gel 60 (Merck, grain size 0.063-0.20 mm). Thefractions containing the product are combined and evaporated, whereupon2-nitro-6-allyloxy-benzyl acetate is obtained as an oil.

(c) 11 ml of 2 N sodium hydroxide solution are added to a solution of5.2 g of 2-nitro-6-allyloxy-benzyl acetate in 90 ml of methanol and themixture is heated to 60° for half an hour. the methanol and part of thewater are then distilled off under reduced pressure, the residue ispartitioned between water and diethyl ether and the ethereal phase iswashed with water, dried over sodium sulphate and evaporated underreduced pressure, whereupon 2-nitro-6-allyloxy-benzyl alcohol isobtained as a yellowish oil.

(d) A mixture of 1 g of Raney nickel and 100 ml of methanol is initiallyintroduced into a reaction vessel and warmed to an internal temperatureof 50°-60°. A solution of 4.4 g of 2-nitro-6-allyloxy-benzyl alcohol and5 ml of hydrazine hydrate in 40 ml of methanol are allowed to run indropwise in the course of 15 minutes, whilst stirring. After theevolution of gas, which initially is vigorous, has subsided, the mixtureis heated under reflux for a further 15 minutes, the catalyst isfiltered off and the filtrate is evaporated, whereupon2-amino-6-allyloxy-benzyl alcohol is obtained as a brownish oil.

(e) A solution of 3.1 g of 2-amino-6-allyloxy-benzyl alcohol in 80 ml ofmethylene chloride is initially introduced, together with a solution of2.2 g of sodium bicarbonate in 100 ml of water, into a reaction vessel.The mixture is cooled to an internal temperature of 0° and a solution of2.8 ml of benzyloxy-carbonyl chloride in 20 ml of methylene chloride isallowed to run in dropwise in the course of 20 minutes, whilst stirring,at such a rate that the temperature does not rise above 0°. The reactionmixture is then stirred for 11/2 hours at 0° and the organic phase isthen separated off, dried over sodium sulphate and evaporated underreduced pressure, whereupon crude2-benzyloxycarbonylamino-6-allyloxybenzyl alcohol is obtained as abrownish oil.

(f) 1.7 ml of a 1 N solution of sodium ethoxide in ethanol are added toa solution of 5.9 g of 2-benzyloxycarbonylamino-6-allyloxy-benzylalcohol in 10 ml of absolute ethanol and the mixture is then heated tothe boil under reflux for 30 minutes. The solvent is then distilled offunder reduced pressure, 1.7 ml of 1 N hydrochloric acid are added to theresidue and the mixture is partitioned between methylene chloride andwater. The organic phase is separated off, washed with water, dried oversodium sulphate and filtered and the filtrate is evaporated. Thecrystalline residue is recrystallised from diethyl ether, whereupon7-allyloxy-4H-1,3-benzoxazin-2(1H)-one with a melting point of 157°-158°is obtained.

(g) 2.0 g of benzonitrile, 5 ml of 30% strength aqueous hydrogenperoxide and 0.3 g of potassium bicarbonate are added to a solution of1.5 g of 7-allyloxy-4H-1,3-benzoxazin-4H-1,3-benzoxazin-2(1H)-one in 60ml of methanol. After stirring at 20° for 60 hours, the solvent islargely distilled off under reduced pressure. The crystals which haveprecipitated out are filtered off and recrystallised from methanol,whereupon 7-(2,3-epoxypropoxy)-4H-1,3-benzoxazin-2(1H)-one with amelting point of 141°-143° is obtained.

EXAMPLE 10

4-(3-tert.-Butylamino-2-hydroxy-propoxy)-3-butyl-benzimidazol-2-one, thehydrochloride of which, after recrystallisation from a mixture ofmethanol and acetone, melts at 226°-227°, is obtained analogously toExample 1 from 4.0 g of 4-(2,3-epoxy-proposy)-3-butyl-benzimidazol-2-oneand 16 ml of tert.-butylamine in 160 ml of isopropanol.

4-(2,3-Epoxy-propoxy)-3-butylbenzimidazol-2-one which is used as thestarting material, can be prepared as follows:

(a) A mixture of 9.0 g of 1-allyloxy-2,3-dinitrobenzene and 40 ml ofn-butylamine in 400 ml of isopropanol is heated under reflux, andstirred, for two hours. After evaporating off the solvent and the excessn-butylamine under reduced pressure, the resulting oil is dried at50°/0.01 mm Hg for 2 hours. The 1-allyloxy-2-butylamino-3-nitrobenzenewhich is thus obtained can be further used without purification.

(b) A suspension of 0.5 g of Raney nickel in 50 ml of tetrahydrofuran iswarmed to 50°, whilst stirring, and a solution of 10.0 g of1-allyloxy-2-butylamino-3-nitrobenzene and 10 ml of hydrazine hydrate in100 ml of tetrahydrofurane is added dropwise in the course of 40minutes. The reaction mixture is then heated to the boil for 1 hour,whilst stirring and under reflux. After cooling, the catalyst isfiltered off, the filtrate is evaporated under reduced pressure and theoily residue is subjected to distillation in a bulb tube,1-allyloxy-2-butylamino-3-aminobenzene being obtained at 100°/0.1 mm Hg(external temperature) as a yellowish distillate.

(c) A mixture of 7.7 g of 1-allyloxy-2-butylamino-3-aminobenzene and 7.1g of N,N'-carbonyldiimidazole in 100 ml of toluene is stirred at 60° for15 hours. The toluene is then distilled off under reduced pressure andthe residue is extracted several times with water and then partitionedbetween water and diethyl ether. The organic phase is dried over sodiumsulphate and partially evaporated, whereupon crystalline4-allyloxy-3-butyl-benzimidazol-2-one with a melting point of 110°-112°is obtained.

(d) 2.2 g of benzonitrile, 5.4 ml of a 30 percent strength aqueoussolution of hydrogen peroxide and 0.3 g of potassium bicarbonate areadded to a suspension of 3.3 g of 4-allyloxy-3-butyl-benzimidazol-2-onein 90 ml of methanol and the mixture is then stirred for 3 days at 20°.The methanol is then virtually completely distilled off under reducedpressure, the residual oil is partitioned between water and diethylether and the organic phase is washed with water, dried over sodiumsulphate and concentrated to a volume of about 15 ml and petroleum etheris added. The resulting crystals are recrystallised from a diethylether/hexane mixture, whereupon4-(2,3-epoxypropoxy)-3-butyl-benzimidazol-2-one with a melting point of90°-92° is obtained.

EXAMPLE 11

4-(3-Isopropylamino-2-hydroxypropoxy)-benzimidazol-2-one, thehydrochloride of which is recrystallised from a mixture of methanol andacetone and has a melting point of 231°-232°, is obtained analogously toExample 1 from 6.6 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one and 20.2ml of isopropylamine in 160 ml of isopropanol.

EXAMPLE 12

4-(3-tert.-Butylamino-2-hydroxypropoxy)-3-methyl-benzimidazol-2-one, thehydrochloride of which, after recrystallisation from a mixture ofmethanol and acetone, melts at 246°-248° (with decomposition), isobtained analogously to Example 1 from 2.85 g of4-(2,3-epoxypropoxy)-3-methyl-benzimidazol-2-one and 15 ml oftert.-butylamine in 150 ml of isopropanol.

4-(2,3-Epoxypropoxy)-3-methyl-benzimidazol-2-one which is used as thestarting material, can be prepared as follows:

(a) A mixture of 9.0 g of 1-allyloxy-2,3-dinitrobenzene, 400 ml ofisopropanol and 12.4 g of gaseous methylamine is heated, in a pressurevessel, to 90° for 3 hours, whilst stirring. After cooling andletting-down, the reaction solution is evaporated under reducedpressure. The resulting oil is dried at 50°/0.01 mm Hg for 2 hours,whereupon 1-allyloxy-2-methylamino-3-nitrobenzene is obtained; this canbe used further without purification.

(b) 1-Allyloxy-2-methylamino-3-aminobenzene, which after distillation ina bulb tube is obtained at 110°-120°/0.1 mm Hg (external temperature) asa yellowish oil, is obtained analogously to Example 10b) from 7.1 g of1-allyloxy-2-methylamino-3-nitrobenzene by reduction by means of 10 mlof hydrazine hydrate and 0.5 g of Raney nickel using the same amount oftetrahydrofurane as the solvent.

(c) 4-Allyloxy-3-methyl-benzimidazol-2-one, which has a melting point of167°-168°, is obtained analogously to Example 10c) from 5.4 g of1-allyloxy-2-methylamino-3-aminobenzene and 6.1 gN,N'-carbonyldiimidazole in 100 ml of toluene, after working up andsubsequently recrystallising from toluene.

(d) Analogously to Example (10d), 2.55 g of4-allyloxy-3-methyl-benzimidazol-2-one are reacted in a mixture of 90 mlof methanol, 2.0 g of benzonitrile, 5.0 ml of a 30 percent strengthaqueous solution of hydrogen peroxide and 0.3 g of potassiumbicarbonate. After removing the methanol, a crystalline precipitate isobtained on the addition of water and after recrystallisation fromaqueous methanol this gives4-(2,3-epoxypropoxy)-3-methyl-benzimidazol-2-one which has a meltingpoint of 165°-166°.

EXAMPLE 13

A mixture of 4.12 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one in 100 mlof isopropanol and 13.52 g of d,1-1-phenyl-2-aminopropane is heated tothe boil under reflux for 4 hours. The solvent is then distilled offunder reduced pressure and subsequently the excess1-phenyl-2-aminopropane is distilled off at 50°/0.01 mm Hg. The residueis dissolved in isopropanol and a solution of the equimolar amount offumaric acid in isopropanol is added, whereupon the 1:14-[3-(1-phenylpropyl-2-amino)-2-hydroxy-propoxy]-benzimidazol-2-onefumarate crystallises out; melting point 186°-188°.

EXAMPLE 14

A mixture of 4.12 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one in 50 mlof isopropanol and 4.0 g of dibenzylamine is heated under reflux for 5hours. The solvent is then distilled off under reduced pressure and theresidue is recrystallised from ethyl acetate, whereupon4-(3-dibenzylamino-2-hydroxypropoxy)-benzimidazol-2-one with a meltingpoint of 201°-202° is obtained.

EXAMPLE 15

0.6 ml of glacial acetic acid and 3.7 ml of acetone are added to asolution of 4.0 g of4-(3-dibenzylamino-2-hydroxypropoxy)-benzimidazol-2-one in 300 ml ofethanol. This solution is added to a pre-hydrogenated suspension of 0.5g of 10 percent strength palladium oxide-on-charcoal and 0.5 g of 10percent strength platinum oxide-on-charcoal. The suspension is shakenunder hydrogen. After the absorption of hydrogen has ceased, thecatalyst is filtered off and rinsed with ethanol and the filtrate isevaporated under reduced pressure. The oily residue is partitionedbetween 10 ml of a saturated aqueous solution of sodium carbonate and 50ml of ethyl acetate. The organic phase is washed with a half-saturatedaqueous solution of sodium chloride, dried over sodium sulphate and thenevaporated under reduced pressure. The residue is dissolved in acetoneand an ethereal solution of hydrogen chloride is added.4-(3-Isopropylamino-2-hydroxypropoxy)-benzimidazol-2-one hydrochlorideis obtained and after recrystallisation from methanol/acetone this meltsat 231°-233° with decomposition.

EXAMPLE 16

1.7 ml of concentrated hydrochloric acid and then 10 ml of a molarsolution of phosgene in toluene are added to 2.5 g of1-(2,3-diaminophenoxy)-2-hydroxy-3-tert.-butylaminopropane and themixture is stirred for 5 hours at 20°. After adding a further 10 ml ofthe phosgene solution, the mixture is stirred for a further 18 hours.The solvent is then distilled off under reduced pressure. The residue isrecrystallised from a mixture of methanol and acetone, whereupon4-(3-tert.-butylamino-2-hydroxypropoxy)-benzimidazol-2-one hydrochloridewith a melting point of 250°-260° (gradual decomposition) is obtained.

1-(2,3-Diamino-phenoxy)-2-hydroxy-3-tert.-butylaminopropane, which isused as the starting material, can be prepared as follows:

(a) A mixture of 65.1 g of 2,3-dinitrophenol, 300 ml of acetone and 47.1g of potassium carbonate is heated under reflux, whilst stirring, and 29ml of allyl bromide are allowed to run in dropwise in the course of onehour. After stirring and heating under reflux for a further 16 hours,the inorganic salts are filtered off and the residue is rinsed withacetone. The filtrate is evaporated under reduced pressure, the residueis taken up in diethyl ether and petroleum ether is added to thesolution, whereupon 1-allyloxy-2,3-dinitrobenzene with a melting pointof 51°-52° crystallises out.

(b) 4.6 g of potassium bicarbonate, 36.0 g of benzonitrile and 60 ml of30% strength hydrogen peroxide are added to a solution of 52.2 g of1-allyloxy-2,3-dinitrobenzene in 450 ml of methanol and the mixture isthen stirred for 4 days at 22°. The resulting crystalline precipitate isfiltered off and recrystallised from methanol, whereupon1-(2,3-dinitrophenxoy)-2,3-epoxypropane with a melting point of 98°-100°is obtained.

(c) Dry carbon dioxide is passed into a solution of 11.4 ml oftert.-butylamine in 40 ml of diethyl ether and a white crystallineprecipitate forms. Carbon dioxide continues to be passed in until thebulk of the ether has volatilised. 24.0 g of1-(2,3-dinitrophenoxy)-2,3-epoxypropane and 300 ml of isopropanol areadded to the resulting residue and the mixture is heated to the refluxtemperature for one hour, while stirring, a clear solution beingobtained. The latter is evaporated under reduced pressure and thecrystalline residue is recrystallised from toluene, whereupon1-(2,3-dinitrophenoxy)-2-hydroxy-3-tert.-butylaminopropane with amelting point of 124°-125° is obtained.

(d) A suspension of 0.5 g of Raney nickel in 20 ml of ethanol is warmedto an internal temperature of 65°-70°, whilst stirring. A solution of2.3 g of 1-(2,3-dinitrophenoxy)-2-hydroxy-3-tert.-butylaminopropane in40 ml of tetrahydrofurane and a solution of 3.6 ml of hydrazine hydratein 40 ml of ethanol are allowed simultaneously to run dropwise, from twodropping funnels, into this suspension. The mixture is then stirred fora further 2 hours at 65°-70°, the catalyst is then filtered off, thefiltrate is evaporated under reduced pressure, the residue is dissolvedin diethyl ether and the ether solution is treated with active charcoaland filtered. After concentrating the filtrate,1-(2,3-diaminophenoxy)-2-hydroxy-3-tert.-butylaminopropane with amelting point of 73°-75° is obtained on the addition of petroleum ether.

EXAMPLE 17

Analogously to Example 13,4-[3-(2-(3,4-dimethoxyphenyl)-ethylamino)-2-hydroxypropoxy]-benzimidazol-2-oneis obtained from 2.8 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one and12.3 g of 2-(3,4-dimethoxyphenyl)-ethylamine and is dissolved in acetoneand an ethereal solution of hydrogen chloride is added to this solution,whereupon the hydrochloride is obtained and this is recrystallised frommethanol/acetone; melting point 230°-232°.

EXAMPLE 18

After adding 2.0 g of palladium-on-charcoal catalyst (5% strength), asolution of 3.22 g of5-(3-benzylisopropylamino-2-hydroxypropoxy)-1,2,3,4-tetrahydro-2,3-dioxo-quinoxazolinehydrochloride hemi-hydrate in 60 ml of water is hydrogenated at roomtemperature and under a pressure of 4 atmospheres. After about 15 hours,the calculated amount of hydrogen has been taken up. The reactionmixture is separated from the catalyst by filtration and the filtrate isevaporated completely under a waterpump vacuum, whereupon5-(3-isopropylamino-2-hydroxypropoxy)-1,2,3,4-tetrahydro-2,3-dioxo-quinoxazolinehydrochloride with a melting point of 290°-294° (decomposition) isobtained.

Recrystallisation from methanol/ether gives the compound with a meltingpoint of 293°-295° (decomposition).

The starting material used can be prepared as follows:

(a) A solution of 5.3 g of 4-(2,3-epoxypropoxy)-benz-2,1,3-thiadiazoleand 3.8 g of N-benzylisopropylamine in 100 ml of isopropanol is boiledunder reflux for 4 hours. The reaction mixture is evaporated under awaterpump vacuum, the residue is dissolved in ether and the solution isextracted with 2 N hydrochloric acid. The combined hydrochloric acidextracts are rendered alkaline with concentrated ammonia and extractedwith ether. The combined ether extracts are washed with water, driedover sodium sulphate and evaporated under a waterpump vacuum, whereupon4-(3-benzylisopropylamino-2-hydroxypropoxy)-benz-2,1,3-thiadiazole isobtained as a yellow oil.

(b) 12.8 g of zinc dust are introduced in 3 portions into a solution of8.7 g of4-(3-benzylisopropylamino-2-hydroxypropoxy)-benz-2,1,3-thiadiazole in110 ml of glacial acetic acid, at room temperature, whilst stirring.After stirring for about 3 hours at room temperature, the reactionmixture is separated from the excess zinc dust by filtration and thefiltrate is evaporated completely under a waterpump vacuum. 15% strengthsodium hydroxide solution is added to the residue and the mixture isextracted with methylene chloride. The combined methylene chlorideextracts are washed with water, dried over sodium sulphate andevaporated under a waterpump vacuum, whereupon3-(3-benzylisopropylamino-2-hydroxypropoxy)-1,2-phenylenediamine with amelting point of 60°-63° is obtained.

(c) 8 g of3-(3-benzylisopropylamino-2-hydroxypropoxy)-1,2-phenylenediamine arestirred with 40 ml of dimethyl oxalate at 100° for 15 hours. Thecrystals which have precipitated are filtered off and washed with ether.The resulting crystals are dissolved in 50 ml of methanol and thesolution is stirred with 5 ml of 2 N sodium hydroxide solution at 60°for 2 hours. The resulting suspension is acidified with 2 N hydrochloricacid and the methanol is evaporated in vacuo. The clear solutioncontaining hydrochloric acid is neutralised with sodium bicarbonatesolution, after which the crystals which have precipitated and are5-(3-benzylisopropylamino-2-hydroxypropoxy)-1,2,3,4-tetrahydro-2,3-dioxo-quinoxazolinewith a melting point of 263°-267° (decomposition) are separated off. Thehydrochloride prepared with methanolic hydrochloric acid crystallisesfrom a water/acetone mixture as the hemi-hydrate with a melting point of250°-252° (decomposition).

EXAMPLE 19

Analogously to Example 17,4-[3-(2-(3,4-methylenedioxyphenyl)-ethylamino)-2-hydroxy-propoxy]-benzimidazol-2-oneis obtained from 2.8 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one and12.3 g of 2-(3,4-methylenedioxy-phenyl)-ethylamine and is dissolved inacetone and an ethereal solution of hydrogen chloride is added to thissolution, whereupon the hydrochloride is obtained; this isrecrystallised from methanol/acetone; the salt sinters at 243° and meltsat 249°-251°.

EXAMPLE 20

A mixture of 2.6 g of8-(2,3-epoxypropoxy)-benzo-[3,2-a]-1,4-oxazin-3[4H]-one, 18.1 g ofhomoveratrylamine and 300 ml of isopropanol is rfluxed with stirring.The solvent is distilled off after 4 hours and, from the oil remainingbehind, the unreacted homoveratrylamine is removed by bulb-tubedistillation at 120°/0.1 Torr. The residue is taken up in 50 ml of hotmethanol; the solution is cooled, and 2.5 ml of a 5 N ethereal hydrogenchloride solution are added. There is obtained a crystallineprecipitate, which is filtered off, and recrystallized from methanol.The8-[3-[2-(3,4-dimethoxyphenyl)-ethylamino]-2-hydroxypropoxy]-benzo[3,2-a]-1,4-oxazin-3[4H]-onehydrochloride thus obtained melts at 195°-196°.

EXAMPLE 21

A solution of 22 g of 4-hydroxyphenoxyethyl bromide in 200 ml of dioxaneis added dropwise, in the course of 30 hours, to a suspension of 22.4 gof 4-(3-amino-2-hydroxypropoxy)benzimidazol-2-one and 21.2 g of sodiumcarbonate in 100 ml of dioxane, which is being stirred under reflux in anitrogen atmosphere. The reaction mixture is subsequently allowed toreact for 5 hours; the inorganic salts are filtered off under suction;the filtrate is concentrated under reduced pressure; the oil remainingbehind is taken up in acetone, and an ethereal hydrogen chloridesolution is added to thus obtain4-[3-[2-(4-hydroxyphenoxy)-ethylamino]-2-hydroxy-propoxy]-benzimidazol-2-onehydrochloride, which melts at 206°-208°.

EXAMPLE 22

5.2 g of4-[3-(N-benzyl-N-[4-benzyloxyphenoxyethyl])-N-2-hydroxypropoxy]-benzimidazol-2-onein 200 ml of ethanol are hydrogenated, using 0.5 g of 5%palladium-on-charcoal catalyst, at 20°-25° under normal pressure. Aftercompletion of the absorption of hydrogen, the catalyst is filtered offwith suction, and the filtrate is concentrated by evaporation. From theresulting residue, dissolved in an acetone/methanol mixture, is preparedthe hydrochloride in the usual manner by the addition of etherealhydrogen chloride solution. There is thus obtained4-[3-[2-(4-hydroxyphenoxy)-ethylamino]-2-hydroxypropoxy]-benzimidazol-2-onehydrochloride, which melts at 206°-208°.

The starting material can be produced as follows:

A mixture of 3.09 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one, 4.99 gof benzylaminoethoxyphenyl-4-benzyl ether and 50 ml of isopropanol isrefluxed with stirring for 2 hours. There is obtained a clear solution,which is subsequently concentrated under reduced pressure. From an ethylacetate/ether mixture, the residue yields4-[3-(N-benzyl-N-[4-benzyloxyphenoxyethyl])-N-2-hydroxypropyl]-benzimidazol-2-one,which melts at 108°-109°.

EXAMPLE 23

In a distilling apparatus, a suspension of 22.4 g of4-(3-amino-2-hydroxypropoxy)-benzimidazol-2-one and 20 g of4-hydroxyphenoxyacetic acid methyl ester in 200 ml of xylene is heatedto boiling whilst being stirred, care being taken to ensure that thetemperature in the distilling head does not exceed 100°. The methanolliberated during the reaction slowly distills over. After 24 hours, thetemperature is so increased that the xylene distills over. Thedistillation residue is dissolved in absolute tetrahydrofuran, and thesolution is slowly added dropwise to a stirred suspension of 7.6 g oflithium aluminium hydride in 200 ml of absolute tetrahydrofuran. Thereaction mixture is subsequently refluxed for 5 hours with stirring; itis then cooled to 0°, and the residue is decomposed by the dropwiseaddition of 80 ml of 12 N hydrochloric acid at a temperature of 0°-5°.There are afterwards added 70 g of Seignette salt, and the reactionmixture is brought to pH 9-10 by the addition of concentrated ammoniasolution. The reaction solution is now a two-phase mixture; the organicphase is separated, dried over sodium sulphate, and concentrated underreduced pressure. The crude4-[3-[2-(4-hydroxyphenoxy)-ethylamino]-2-hydroxypropoxy]-benzimidazol-2-oneremaining yields, with hydrochloric acid, the hydrochloride which, afterrecrystallisation form acetone, melts at 206°-208°.

The 4-(3-amino-2-hydroxypropoxy)-benzimidazol-2-one used as startingmaterial can be produced as follows:

(a) 3.3 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one and 11.8 g ofbenzylamine in 80 ml of isopropanol are refluxed for 5 hours. Thesolvent together with the unreacted benzylamine are then distilled off,and the oil remaining is dried at 90°/0.001 Torr for 2 hours. Itconsists of 4-(3-benzylamino-2-hydroxypropoxy)-benzimidazol-2-one which,from water, is obtained in the form of crystals; after drying at 60°/1Torr for 18 hours, these melt at 203°-205°.

The hydrochloride melts at 231°-232° with decomposition.

(b) 1.6 g of palladium-on-charcoal catalyst are added to a solution of15.5 g of 4-(3-benzylamino-2-hydroxypropoxy)benzimidazol-2-one in 160 mlof methanol, and the mixture is hydrogenated until the calculated amountof hydrogen has been absorbed. The catalyst is filtered off and thesolvent distilled off to leave4-(3-amino-2-hydroxypropoxy)-benzimidazol-2-one, which melts at188°-190° after recrystallization from ethanol.

The hydrochloride melts at 232°-239°.

EXAMPLE 24

9.5 g of4-[3-[N-benzyl-N-[2-(2-benzyloxyphenoxy)ethylamino]-2-hydroypropoxy]-benzimidazol-2-oneare dissolved with the addition of 18 ml of methanolic 1 N hydrogenchloride solution, in 100 ml of methanol, and hydrogenated, using 0.5 gof 5% palladium-on-charcoal catalyst, at 20°-25° under normal pressure.After completion of the absorption of hydrogen, a mixture of methanoland water (1:1, v/v) is added until the precipitate is dissolved.Thereafter the catalyst is filtered off with suction, and the filtrateis concentrated by evaporation. The resulting residue is recrystallizedfrom hot water. There is thus obtained4-[3-[2-(2-hydroxyphenoxy)-ethylamino]-2-hydroxypropoxy]-benzimidazol-2-onehydrochloride, which melts at 256°-257°.

The starting material can be produced as follows:

A mixture of 6.86 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one 11.1 g ofbenzylaminoethoxyphenyl-2-benzyl ether and 50 ml of isopropanol isrefluxed with stirring for 3 hours. The solvent is distilled of underreduced pressure and the residue is dissolved in hot methanol. Uponcooling 4-[3-[N-midazol-2-one crystallises and is filtered off. It meltsat 152°-153°.

What is claimed is:
 1. A compound of the formula ##STR14## in which R₁denotes optionally substituted lower alkyl which is optionally branchedat the linking carbon atom, R₂ represents hydrogen or lower alkanoyl andR₃ is a group of the formula --CO--NH-- or of the formula --CH₂ --NH--in the form of a racemate, optical antipode or an acid addition saltthereof which can be used pharmaceutically.
 2. A compound as claimed inclaim 1 in which R₁ denotes lower alkyl with 3-5 carbon atoms which isoptionally branched at the linking carbon atom and can be substituted,on a carbon atom other than the linking carbon atom, by phenyl whichoptionally contains hydroxyl, as well as lower alkyl, lower alkoxy,methylenedioxy or halogen, or by phenoxy which optionally containscarbamoyl, R₂ represents hydrogen and R₃ represents the group of theformula --CO--NH-- or of the formula --CH₂ --NH-- the form or aracemate, optical antipodes or an acid addition salt thereof which canbe used pharmaceutically.
 3. A compound as claimed in claim 1 in whichR₁ denotes lower alkyl with 3-5 carbon atoms which is optionallybranched at the linking carbon atom or denotes 2-phenyl-lower alkyl, inwhich lowr alkyl contains up to 3 carbon atoms, which is optionallysubstituted in the phenyl part by lower alkoxy or methylenedioxy, R₂represents hydrogen and R₃ denotes the group of the formula --CO--NH--or of the formula --CH₂ --NH-- in the form of a racemate, opticalantipodes or an acid addition salt thereof which can be usedpharmaceutically.
 4. A compound as claimed in claim 1 which is5-(3-tert.butylamino-2-hydroxy-propoxy)-3,4-dihydro-1H-quinazolin-2-onein the form of a racemate, optical antipodes or an acid addition saltthereof which can be used pharmaceutically.
 5. A compound as claimed inclaim 1 which is5-(3-tert.-butylamino-2-hydroxypropoxy)-(1H)-quinazoline-2,4-dione inthe form of a racemate, optical antipodes or an acid addition saltthereof which can be used pharmaceutically.
 6. The hydrochloride salt ofthe compound of claim
 4. 7. The hydrochloride salt of the compound ofclaim
 5. 8. A pharmaceutical composition useful in the treatment ofdisorders in the cardiac rhythm and coronary heart diseases as well asof hypertension comprising a therapeutically effective amount of acompound as claimed in claim 1, or an acid addition salt thereof whichcan be used pharmaceutically, together with a pharmaceuticallyexcipient.
 9. A method for the treatment of disorders in the cardiacrhythm and coronary heart diseases as well as of hypertension in awarm-blooded animal which comprises the administration thereto of atherapeutically effective amount of a compound defined in claim 1.